The compounds of formula (I) are activators for peroxisome proliferator-activated receptors (PPAR activators) and are already known from WO 03/020269. Of the PPAR activators described in WO 03/020269, effective PPAR activators have been found to be those which have a cis substitution of the X- and Y-containing substituent on the central ring A. This applies in particular to compounds in which the ring A=cyclohexyl, preferably cis-1,3-cyclohexyl.
In the synthesis and isolation of the desired target molecules of formula (I), principally two factors present difficulties. One is the cis/trans isomerism of the substituents of ring A. Since, in the case of the compounds of the formula (I), the cis-isomers are more effective PPAR activators than the corresponding trans-isomers, it is advisable to remove the particular trans-isomers of the ring A in the corresponding intermediates actually at the start of the synthesis in order to avoid unnecessary yield losses. Secondly, considering only the cis-isomer of the ring A, it also must to be taken into account that two chiral carbon atoms are present in most intermediates and in the target molecule of the of the formula (I), it must also be recognized that ring A is substituted by two different radicals (X, Y). Consequently, in the connection of ring A with, for example, the X-containing substituent, a racemic mixture is formed in an equimolar reaction because this substituent can in principle be connected to both functional groups of ring A. If no allowance is made for this, the compounds of the formula (I) are also present as a racemic mixture.
Although it is possible using the preparation process described in WO 03/020269 for PPAR activators to prepare the compounds of the formula (I) in enantiomerically pure form in principle, the process described therein has some significant disadvantages. Poisonous tin compounds, cesium fluoride and iodide-containing compounds are used in the reaction and disposal of these is also necessary. The process involves a racemic synthesis, i.e., after removal of the enantiomer (which is not required by chiral chromatography), at least half of the expensive starting materials are lost as waste. Moreover, the chiral chromatography additionally has to be linked to achiral chromatography; half of the product or the valuable starting materials used therefore are lost in a racemate separation into two enantiomers. The “wrong” enantiomer cannot be recycled and has to be disposed of as waste. Finally, the process requires the use of sodium hydride as a base and N,N-dimethylformamide as a solvent both of which may result in potentially exothermic decomposition.
In order to be able to prepare an enantiomeric excess or an enantiomerically pure compound of formula (I), chiral chromatography is absolutely necessary in the process described in WO 03/020269. Especially on the industrial scale, the high costs associated with chiral chromatography are found to be the main disadvantage of this process.
An alternative process for preparing the PPAR activators as disclosed in WO 03/020269 is described in the international application WO10/308350.2. In this process, which is restricted to the preparation of cis-1,3-disubstituted cyclohexane derivatives, cis-1,3-cyclohexanediol is initially alkylated either with a protecting group (benzyl or silyl) or one of the two substituents of the target molecule, in which case the racemic mixture of the corresponding monoalkylated cis compound is formed. This intermediate is in turn reacted with an acyl donor, and this monoalkylated and monoacylated intermediate which is also present as a racemate is separated via an enzymatic ester cleavage and subsequent chromatography into two fractions from which the two enantiomers of the target molecule can each be synthesized separately. Alternatively, the racemic monoalkylated intermediate can be separated by enzymatic ester formation and subsequent chromatography into two fractions from which the two enantiomeric forms of the target molecule can in turn be synthesized in two separate batches. A disadvantage in this process is that in spite of the avoidance of chiral chromatography, a racemic intermediate is initially formed, from which the two enantiomeric forms of the target molecule inevitably are produced. When the synthesis variant is utilized by means of the protecting group introduced first, the benzyl-containing protecting groups have to be removed by hydrogenation. In this hydrogenation, the first substituent of the target molecule which has already been bonded to the corresponding intermediate may be removed again to a certain degree, which leads to a yield loss. Silyl-containing protecting groups are removed with fluoride, but this too leads to further side reactions in the remaining substituents of the corresponding intermediates and should consequently be avoided.
The use of enzymes to separate racemic mixtures of various compounds (starting materials or intermediates) is well known in the art. However, the discovery of suitable enzymes for the enantioselective separation of the racemic mixture to be separated in each case presents particular difficulties.
For instance, T. Hirata et al., Chirality 9: 250-253 (1997) describes the hydrolysis of cis- and trans-1,3-diacetoxycyclohexane to acyloxycyclohexanols in the presence of cultivated plant cells from common liverwort (Marchantia polymorpha). However, to achieve this, the cultivation of the plant cells is necessary; the accompanying enzymes are not known. The enantiomeric excess in the hydrolysis of meso-cis-1,3-diacetoxycyclohexane here is only 15% for (1R,3S)-1-acetoxycyclohexan-3-ol. trans-1,3-Diacetoxycyclohexane is converted to (1R,3R)-3-acetoxycyclohexan-1-ol (60% yield) with 27% enantiomeric excess and cyclohexane-1,3-diol (70% yield). This method is therefore not suitable for preparing an acceptable enantiomeric excess or enantiomerically pure cis-1S-acyloxycyclohexan-3R-ol.
K. Laumen et al., J. Chem. Soc., Chem. Common., (1986) 1298-1299 describe the enzymatic hydrolysis of cis-1,4-diacetoxycyclopent-2-ene in the presence of lipases such as Pseudomonas species or Mucor miehei. At a conversion of approx. 50%, a monoacylated enantiomer with an enantiomeric purity of from 95 to 97% is formed. The enantiomeric purity can be increased to above 99% by recrystallization.